As methods for producing an alkyl (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6-heptenoate of the formula (1) (wherein R is a C1-4 alkyl group), the following methods (a) to (c) by optical resolution of its racemic modification and the following methods (d) to (f) by an asymmetric synthesis, are known.
(a) A method for producing it by an optical resolution of its racemic modification by means of a high performance liquid chromatography (HPLC) column (such as CHIRALCEL OF, manufactured by Daicel Chemical Industries, Ltd.) for separation of optical isomers (e.g. International Patent Publication No. 95/23125, U.S. Pat. No. 5,939,552).
(b) A method for optical resolution of a racemic modification by means of an enzyme (e.g. JP-A-2001-352996).
(c) A method wherein the racemic modification is hydrolyzed, and the obtained carboxylic acid are subjected to optical resolution by means of a resolving agent such as an optically active α-methylbenzylamine, followed by esterification (e.g. JP-A-5-148237, U.S. Pat. No. 5,284,953).
(d) A method for producing it by means of a chiral synthon of the formula (4) (e.g. JP-A-8-127585).

(e) A method of chemically selectively reducing an alkyl 7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-5-hydroxy-3-oxo-6-heptenoate of the formula (5) (wherein R is as defined above) obtainable by e.g. an asymmetric aldol reaction (e.g. JP-A-8-92217). The compound of the formula (5) can be obtained by an asymmetric synthesis (e.g. International Patent Publication No. 03/042180).

(f) A method of selectively reducing an optically active compound of the formula (5) or an alkyl 7-[2-cyclopropyl-4-(4-fluorophenyl)quinoline-3,5-dioxo-6-heptenoate of the formula (6) (wherein R is as defined above) by a biochemical technique (e.g. International Patent Publication No. 02/063028).

By the above-mentioned method (a) or (b), by recrystallizing the racemic modification corresponding to the compound of the formula (1), its epimers (a 1:1 mixture of compounds of the formulae (2) and (3)) can easily be removed, whereby the compound of the formula (1) of high purity can be obtained without separating the epimers after the optical resolution. However, such a technique by optical resolution of the racemic modification has an essential problem that its antipode (an alkyl (3S,5R)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6-heptenoate) will be wasted. By the method (c), the two types of epimers can be removed together with the antipode in the step for the resolution of diastereomers, whereby no purification of the racemic modification is required. However, this method is also essentially a resolution method of the racemic modification and thus has the same essential drawback as the methods (a) and (b).

The above methods (c) to (f) are production methods via an optically active compound of the formula (5) or (7), but neither the chemical reaction method nor the biochemical reduction method is a completely selective reaction, whereby inclusion of a small amount of epimers is unavoidable. To secure the quality useful as an intermediate for pharmaceuticals, it is necessary to remove such epimers, but, as is different from the racemic modification, the optically active substance of the formula (1) is a compound which is extremely difficult to purify by recrystallization. A purification method by leading it to a p-toluene sulfonate or the like, has also been tried, but the purpose has not been accomplished in any case for such a reason that lactone-modification tends to proceed during the purification operation.
However, by each of the asymmetric synthesis and the chiral synthon method, the optically active compound of the formula (5) or (7) can be produced with a high optical purity, whereby the antipode will not be wasted. Accordingly, if it can be established as an industrial production method, the economical effects will be substantial. Therefore, it has been desired to establish an efficient purification method for the compound of the formula (1).
